The effect of aspirin and low-molecular-weight heparin on venous thromboembolism after knee replacement: a non-randomised comparison using National Joint Registry Data.

We compared thromboembolic events, major haemorrhage and death after knee replacement in patients receiving either aspirin or low-molecular-weight heparin (LMWH). Data from the National Joint Registry for England and Wales were linked to an administrative database of hospital admissions in the English National Health Service. A total of 156,798 patients between April 2003 and September 2008 were included and followed for 90 days. Multivariable risk modelling was used to estimate odds ratios adjusted for baseline risk factors (AOR). An AOR < 1 indicates that risk rates are lower with LMWH than with aspirin. In all, 36,159 patients (23.1%) were prescribed aspirin and 120,639 patients (76.9%) were prescribed LMWH. We found no statistically significant differences between the aspirin and LMWH groups in the rate of pulmonary embolism (0.49% vs 0.45%, AOR 0.88 (95% confidence interval (CI) 0.74 to 1.05); p = 0.16), 90-day mortality (0.39% vs 0.45%, AOR 1.13 (95% CI 0.94 to 1.37); p = 0.19) or major haemorrhage (0.37% vs 0.39%, AOR 1.01 (95% CI 0.83 to 1.22); p = 0.94). There was a significantly greater likelihood of needing to return to theatre in the aspirin group (0.26% vs 0.19%, AOR 0.73 (95% CI 0.58 to 0.94); p = 0.01). Between patients receiving LMWH or aspirin there was only a small difference in the risk of pulmonary embolism, 90-day mortality and major haemorrhage. These results should be considered when the existing guidelines for thromboprophylaxis after knee replacement are reviewed

The effect of high dose antibiotic impregnated cement on rate of surgical site infection after hip hemiarthroplasty for fractured neck of femur : a protocol for a double-blind quasi randomised controlled trial

Background: Mortality following hip hemiarthroplasty is in the range of 10-40% in the first year, with much attributed to post-operative complications. One such complication is surgical site infection (SSI), which at the start of this trial affected 4.68% of patients in the UK having this operation. Compared to SSI rates of elective hip surgery, at less than 1%, this figure is elevated. The aim of this quasi randomised controlled trial (RCT) is to determine if high dose antibiotic impregnated cement can reduce the SSI in patients at 12-months after hemiarthroplasty for intracapsular fractured neck of femur. Methods: 848 patients with an intracapsular fractured neck of femur requiring a hip hemiarthroplasty are been recruited into this two-centre double-blind quasi RCT. Participants were recruited before surgery and quasi randomised to standard care or intervention group. Participants, statistician and outcome assessors were blind to treatment allocation throughout the study. The intervention consisted of high dose antibiotic impregnated cement consisting of 1 gram Clindamycin and 1 gram of Gentamicin. The primary outcome is Health Protection Agency (HPA) defined deep surgical site infection at 12 months. Secondary outcomes include HPA defined superficial surgical site infection at 30 days, 30 and 90-day mortality, length of hospital stay, critical care stay, and complications. Discussion: Large randomised controlled trials assessing the effectiveness of a surgical intervention are uncommon, particularly in the speciality of orthopaedics. The results from this trial will inform evidence-based recommendations for antibiotic impregnated cement in the management of patients with a fractured neck of femur undergoing a hip hemiarthroplasty. If high dose antibiotic impregnated cement is found to be an effective intervention, implementation into clinical practice could improve long-term outcomes for patients undergoing hip hemiarthroplasty

Independent predictors of failure up to 7.5 years after 35 386 single-brand cementless total hip replacements: a retrospective cohort study using National Joint Registry data

The popularity of cementless total hip replacement (THR) has surpassed cemented THR in England and Wales. This retrospective cohort study records survival time to revision following primary cementless THR with the most common combination (accounting for almost a third of all cementless THRs), and explores risk factors independently associated with failure, using data from the National Joint Registry for England and Wales. Patients with osteoarthritis who had a DePuy Corail/Pinnacle THR implanted between the establishment of the registry in 2003 and 31 December 2010 were included within analyses. There were 35 386 procedures. Cox proportional hazard models were used to analyse the extent to which the risk of revision was related to patient, surgeon and implant covariates. The overall rate of revision at five years was 2.4% (99% confidence interval 2.02 to 2.79). In the final adjusted model, we found that the risk of revision was significantly higher in patients receiving metal-on-metal (MoM: hazard ratio (HR) 1.93, p < 0.001) and ceramic-on-ceramic bearings (CoC: HR 1.55, p = 0.003) compared with the best performing bearing (metal-on-polyethylene). The risk of revision was also greater for smaller femoral stems (sizes 8 to 10: HR 1.82, p < 0.001) compared with mid-range sizes. In a secondary analysis of only patients where body mass index (BMI) data were available (n = 17 166), BMI ≥ 30 kg/m2 significantly increased the risk of revision (HR 1.55, p = 0.002). The influence of the bearing on the risk of revision remained significant (MoM: HR 2.19, p < 0.001; CoC: HR 2.09, p = 0.001). The risk of revision was independent of age, gender, head size and offset, shell, liner and stem type, and surgeon characteristics. We found significant differences in failure between bearing surfaces and femoral stem size after adjustment for a range of covariates in a large cohort of single-brand cementless THRs. In this study of procedures performed since 2003, hard bearings had significantly higher rates of revision, but we found no evidence that head size had an effect. Patient characteristics, such as BMI and American Society of Anesthesiologists grade, also influence the survival of cementless components

Long-term durability of alumina ceramic heads in THA

Background: The optimal type of bearing for hip arthroplasty remains a matter of debate. Ceramic-on-polyethylene (CoP) bearings are frequently used in younger and more active patients to reduce wear and increase biocompatibility compared to Metal-on-Polyethylene (MoP) bearings. However, in comparison to metal heads, the fracture risk of ceramic heads is higher. In addition, ceramic head fractures pose a serious complication which often necessitates major revision surgery. To date, there are no long-term data (>20 years of follow-up) reporting fracture rates of the ceramic femoral heads in CoP bearings. The purpose of this research was to investigate long-term CoP fracture rate. Methods: We evaluated the clinical and radiographic results of 348 cementless THAs treated with 2nd generation Biolox® Al2O3 Ceramic-on-Polyethylene (CoP) bearings consecutively implanted between January 1985 and December 1989. The mean age at implantation was 57 years. The patients were followed for a minimum of 20 years. At the final 111 had died, and 5 were lost to follow-up. The cumulative incidence of ceramic head fractures in the long-term was estimated using a competing risk analysis. Results: The cumulative incidence of ceramic head fracture after 22-years was estimated with a competing risk analysis at 0.29% after 22-years (SE = 2.09%; 95% - CI: 0.03-1.5%). The radiographic analysis revealed no impending failures at final follow-up. Discussion/Conclusion: The fracture rate of second-generation ceramic heads using a CoP articulation remains very low into the third decade after cementless THA

Targeting the hypoxic fraction of tumours using hypoxia activated prodrugs

The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high priority target and one therapeutic strategies designed to eradicate hypoxic cells in tumours are a group of compounds known collectively as hypoxia activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (i) the ability of oxygen to either reverse or inhibit the activation process and (ii) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

The role of γδ T cells in airway epithelial injury and bronchial responsiveness after chlorine gas exposure in mice

BACKGROUND: Acute exposure to chlorine (Cl(2)) gas causes epithelial injury and airway dysfunction. γδ T cells are present in the mucosal surface of the airways and may contribute to the injury/repair response of the epithelium. METHODS: C57Bl/6J (wild type) and TCR-δ(-/- )mice exposed to Cl(2 )(400 ppm) for 5 minutes underwent measurements of airway responses to i.v. methacholine (MCh) at 1, 3, and 5 days after exposure. Bronchoalveolar lavage was performed to determine epithelial and leukocyte counts, and protein content. Tissue repair was assessed by proliferating cell nuclear antigen (PCNA) immunoreactivity and by expression of keratinocyte growth factor (KGF) mRNA by real-time PCR. RESULTS: Wild type mice developed a greater degree of airway hyperresponsiveness to MCh at 1 day post exposure to Cl(2 )compared with TCR-δ(-/- )mice. Epithelial cell counts in BAL after Cl(2 )exposure were greater in TCR-δ(-/- )mice, but macrophages showed a later peak and granulocyte numbers were lower in TCR-δ(-/- )than in wild type mice. Both groups had increased levels of total protein content in BAL after Cl(2 )exposure that resolved after 3 and 5 days, respectively. Epithelial proliferating cell nuclear antigen staining was increased at 1 and 3 days post exposure and was similar in the two groups. KGF mRNA was constitutively expressed in both groups and did not increase significantly after Cl(2 )but expression was lower in TCR-δ(-/- )mice. CONCLUSION: The severity of airway epithelial injury after Cl(2 )is greater in TCR-δ(-/- )mice but the inflammatory response and the change in airway responsiveness to methacholine are reduced. The rates of epithelial regeneration are comparable in both groups

Temporal Regulation of Rapamycin on Memory CTL Programming by IL-12

Mammalian target of rapamycin (mTOR) is a master regulator of cell growth. Recent reports have defined its important role in memory cytotoxic T lymphocyte (CTL) differentiation in infections and memory programming. We report that rapamycin regulated memory CTL programming by IL-12 to a similar level in a wide range of concentrations, and the enhanced memory CTLs by rapamycin were functional and provided similar protection against Listeria Monocytogenes challenge compared to the control. In addition, rapamycin-experienced CTLs went through substantially enhanced proliferation after transfer into recipients. Furthermore, the regulatory function of rapamycin on CD62L expression in memory CTLs was mainly contributed by the presence of rapamycin in the first 24-hr of stimulation in vitro, whereas the effective window of rapamycin on the size of memory CTLs was determined between 24 to 72 hrs. In conclusion, rapamycin regulates IL-12-driven programming of CTLs to a similar level in a wide range of concentrations, and regulates the phenotype and the size of memory CTLs in different temporal windows

Erythromycin lacks colon prokinetic effect in children with functional gastrointestinal disorders: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Motilin, a peptide hormone has a direct excitatory effect on circular smooth muscle strips derived from the human colon. Reduced plasma motilin concentration has been reported in adults with chronic constipation. Erythromycin, a non-peptide motilin receptor agonist, induces phase 3 of the migrating motor complex (MMC) in the antro-duodenum and also reduces oro-cecal transit time. A pediatric study has reported an improvement in clinical symptoms of constipation following erythromycin administration, but the effect on colon motility in children has not been formally evaluated. We used colon manometry to study the effect of intravenous erythromycin lactobionate at 1 mg/kg on colon motiltiy in ten children.</p> <p>Methods</p> <p>We selected patients with normal antroduodenal and colon manometry studies that were performed simultaneously. All studies were performed for clinically indicated reasons. We quantified the effect of erythromycin on colon contraction by calculating the area under the curve (AUC).</p> <p>Results</p> <p>The mean (SE of mean) AUC in the colon during the fasting, post-erythromycin and postprandial phases of the study was 2.1 mmHg/sec (0.35), 0.99 mmHg/sec (0.17) and 3.05 mmHg/sec (0.70) respectively. The AUC following erythromycin was significantly less compared to the fasting phase of the study (p < 0.01).</p> <p>Conclusion</p> <p>Erythromycin lacks colon prokinetic effect in children with chronic constipation evaluated by colon manometry.</p